Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS5324514 A
Publication typeGrant
Application numberUS 08/104,655
Publication dateJun 28, 1994
Filing dateAug 11, 1993
Priority dateJun 22, 1992
Fee statusPaid
Also published asCA2096002A1, CA2096002C, EP0576938A1, US5260074
Publication number08104655, 104655, US 5324514 A, US 5324514A, US-A-5324514, US5324514 A, US5324514A
InventorsTibor Sipos
Original AssigneeDigestive Care Inc.
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Compositions of digestive enzymes and salts of bile acids and process for preparation thereof
US 5324514 A
Abstract
Disclosed are gastric acid-resistant polymer-coated digestive enzymes/ursodeoxycholate compositions, process for their preparations and methods of treating digestive disorders, treating impaired liver function, treating cystic fibrosis, regulating the absorption of dietary cholesterol, and for dissolving gallstones by administering the compositions to a mammal in need of such treatment.
Images(7)
Previous page
Next page
Claims(8)
What is claimed is:
1. A digestive enzyme/bile salt composition for the treatment of digestive enzyme/bile salt deficiency of mammals comprising, by weight per weight percentages based on the total weight of the composition:
a) from about 71 to about 90.0% of a concentrate of an enzyme selected from the group consisting of pancreatic proteases, lipases, nucleases and amylases;
b) from about 0.3 to about 13% of a bile salt in powder form;
c) from about 0.8 to about 5% of a buffering agent consisting of anhydrous sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate in combination with about 0.8 to about 1.5% tromethamine, diethanolamine or triethanolamine;
d) from about 0.9 to about 16% of a disintegrant selected from the group consisting of starch, modified starches, microcrystalline cellulose and propylene glycol alginate;
e) from about 0.3 to about 19.0% of an adhesive polymer selected from the group consisting of hydroxypropyl cellulose, polyvinylpyrrolidone, cellulose acetate phthalate, methyl cellulose and propylene glycol alginate; and
f) from about 7.0 to about 15% of an non-porous, gastric acid-resistant and pharmaceutically acceptable polymer-coating which contains of from about 0.2 to about 2% talc and which is insoluble in the pH range of from about 1.5 to about 5 but is soluble in the pH range of from about 5.5 to about 9.
2. The composition of claim 1 wherein said digestive enzyme is selected from the group consisting of pancreatin, pancrelipase, trypsin, chymotrypsin, chymotrypsin B, pancreatopeptidase, carboxypeptidase A, carboxypeptidase B, glycerol ester hydrolase, phospholipase A2, sterol ester hydrolase, ribonuclease dioxyribonuclease, α-amylase, papain, chymopapain, bromelain, picin, β-amylase, cellulase and β-galactosidase.
3. The composition of claim 1 wherein the salt component of said bile acid is selected from the group consisting of sodium, potassium, ammonium, tromethamine, ethanolamine, diethanolamine and triethanolamine.
4. The composition of claim 3 wherein said bile salt is selected from the group consisting of ursodeoxycholate, ethyl ester of ursodeoxycholate, propyl ester of ursodeoxycholate, glycyl ursodeoxycholate, tauroursodeoxycholate, N-methylglycyl ursodeoxycholate and N-methyltaurine ursodeoxycholate.
5. A method for treating digestive enzyme/bile salt deficiency in mammals comprising: orally administering a therapeutically effective amount of the composition of claim 1.
6. The method of claim 5 wherein about 0.5 to 1.5 gms of the composition is administered to a digestive enzyme/bile salt deficient patient with each meal three times a day.
7. The method of claim 6 wherein said composition is administered in an acid soluble capsule containing from about 0.2 to about 0.5 grams of microspheres or microtablets.
8. The method of claim 6 wherein said composition is administered admixed with a liquid or a semi-solid food.
Description

This application is a divisional application of Ser. No. 07/901,734, filed Jun. 22, 1992, now U.S. Pat. No. 5,260,074.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to digestive enzymes and salts of bile acids, and more particularly salts of ursodeoxycholic acid compositions for ingestion by a mammal, a process for preparing said compositions, and a method for treating digestive disorders, impaired liver function, cystic fibrosis, regulating dietary cholesterol absorption and for dissolving gallstones by administering said compositions to a mammal in need of such treatment.

2. Reported Developments

It is known in the prior art that pancreatic enzymes administered to mammals can remedy enzyme deficiency caused by various diseased conditions of the pancreas, such as cystic fibrosis, pancreatitis, pancreatic enzyme deficiency and old age. Oral administration of compositions containing these enzymes requires the presence of certain conditions in order for them to be safe and effective as will be described hereunder.

Pancreatic enzymes produced by the patient's pancreas are released into the duodenum, the pH of which is close to neutral or slightly alkaline. Under these pH conditions the enzymes are active and digestion of the food by the enzymes proceeds normally in the upper segment of the intestine. However, when pancreatic enzymes are administered exogenously to the patient, the gastric conditions in the stomach, namely the presence of acid and pepsin, will irreversibly inactive the enzymes. Therefore, orally administered enzymes must be protected against gastric inactivation so that they remain intact during their transit through the stomach into the duodenum.

Once the exogenously introduced enzymes reach the duodenum, another requirement must be satisfied: the enzymes must be released from their protective environment and intimately mixed with the food transferred from the stomach to effect digestion.

U.S. Pat. No. 4,079,125 incorporated herein by reference, addresses these requirements in a composition containing these enzymes and provides preparative methods for making the compositions. The compositions provided by said patent comprise: an enzyme concentrate in a binder selected from the group consisting of polyvinylpyrrolidone, microcrystalline cellulose, cellulose acetate phthalate, methylcellulose and alginic acid; a stabilizer selected from the group consisting of calcium carbonate, polyvinylpyrrolidone, cellulose acetate phthalate, methylcellulose, starch and modified starches and alginic acid; a disintegrant selected from the group consisting of citric acid, sodium carbonate, sodium bicarbonate, calcium carbonate, starch and modified starches and alginic acid; said mixture is coated with a non-porous, pharmaceutically acceptable enteric coating polymer which is insoluble in the pH range of from about 1.5 to about 5 normally present in gastric fluids, and soluble at a pH of from about 6 to about 9, the normal pH range for mammalian intestinal fluids.

The orally administered composition passes through the stomach while being protected against the acidic environment by its acid-insoluble coating which then disintegrates in the neutral to basic environment of the upper intestine releasing the enzymes from the composition. The process of making the compositions includes the provision of using a solvent and avoiding the presence of water in the blending step of the enzyme/binder/disintegrant, since it is believed that water deactivates some of the enzymes.

Contrary to the teaching of U.S. Pat. No. 4,079,125, it has now been discovered that the complete exclusion of the water (anhydrous condition) during the process of preparing the enzymes/salts of ursodeoxycholic acid compositions in the form of microtablets and microspheres, leads to products that are extremely friable, tend to crumble into pieces upon drying in a fluidized bed dryer or conventional coating pan and disintegrates upon initiation of the polymer coating step. This results in large amounts of dust and agglomeration of the beads into multiplets during the process as well as improper doses of the enzymes upon administration to the patient when quality control fails to adequately sort-out and discard rejects.

It is also known that ursodeoxycholic acid (hereinafter UDCA or bile acid) is capable of augmenting liver function, dissolving gallstones and improving the nutritional state of patients having cystic fibrosis caused by hepatobiliary complications. See for example, Ursodeoxycholic Acid Dissolution of Gallstones in Cystic Fibrosis, Sahl, B., Howat, J., Webb, K., Thorax, 43:490-1 (1988); Effects of Ursodeoxycholic Acid Therapy for Liver Disease Associated with Cystic Fibrosis, Colombo, C., Setchell, K. D., Podda, M., Crosignani, A., Roda A., Curcio, L., Ronchi, M. and Giunta, A., The Journal of Pediatrics, 117:482-489 (1990); Effects of Ursodeoxycholic Acid Treatment on Nutrition and Liver Function in Patients with Cystic Fibrosis and Longstanding Cholestasis. Cotting, J., Lentze, M. J. and Reichen, J., Gut 31:918-921 (1990). Also, UDCA has recently gained acceptance as an effective therapeutic modality to dissolve small to medium size cholesterol gallstones in gallstone afflicted patients. See for example, The Effect of High and Low Doses of Ursodeoxycholic Acid on Gallstone Dissolution in Humans, Salen, G., Colalillo, A., Verga, D., Bagan, E., Tint, G. S. and Shefer, S., Gastro., 78:1412-1418 ( 1980); Ursodeoxycholic Acid: A Clinical Trial of a Safe and Effective Agent for Dissolving Cholesterol Gallstones, Tint, G. S., Salen, G., Colalillo, A., Graber, D., Verga, D. Speck, J. and Shefer, S., Annals of Internal Medicine, 91:1007-1018 (1986); Clinical Perspective on the Treatment of Gallstones with Ursodeoxycholic Acid, Salen, G., J. Clin. Gastroenterology, 10 (Suppl. 2): S12-17 (1988); Nonsurgical Treatment of Gallstones, Salen, G. and Tint, G. S., New England J. Med., 320:665-66 (1989); and Reducing Cholesterol Levels, Weigand, A. H., U.S. Pat. No. 3,859,437. The recommended dosage is 10 to 15 mg/kg of body weight. In some patients much higher dosages (for example, about 30 mg/kg of body weight) are required to achieve limited benefits. However, in some patients undesirable side effects (such as, severe diarrhea) seriously limit the use of this drug. The reasons for this wide variation of dosage requirements for therapeutic effectiveness and associated side effects are not completely understood. One hypothesis is that the free acidic form of UDCA is only partially neutralized in the upper intestine to its sodium salt form. The residual free acidic form of UDCA is poorly absorbed from the intestine, and a good portion of the administered dosage is excreted intact with feces. When a higher dosage of the acidic form of UDCA is administered to the patient, a large portion of it is neutralized in the distal parts of the intestine which in turn induces diarrhea, a highly undesirable side effect. Also, if the acidic form of UDCA is to be converted into its salt form in the duodenum, it will temporarily exhaust the buffering capacity of the duodenum and it will render the upper intestine partially acidic. The acidic pH impedes the function of the pancreatic enzymes and UDCA cannot emulsify fats and facilitate the hydrolysis of lipids. Furthermore, the many therapeutic benefits derived from the salt forms of UDCA cannot be realized. It should then follow, accordingly, that the salt forms of UDCA should be administered to patients in need of UDCA. U.S. Pat. No. 3,859,437 recommends the administration of a "small but effective amount sufficient to effect a reduction in the cholesterol level of said human being of the compound 3α 7β-dihydroxy-5β-cholanic acid (UDCA) and the non-toxic pharmaceutically acceptable salts thereof". However, administering the salt form of UDCA to patients has no advantage over the acidic form of UDCA and does not accomplish the desired results since the salt form of UDCA is converted back to the insoluble acidic form of UDCA by gastric acidity. Furthermore, the salt forms, i.e., sodium or potassium, of UDCA are extremely bitter-tasting, and in most patients cause esophageal reflux, nausea and vomiting. Because of these highly undesirable organoleptic and gastric side effects, the salt forms of UDCA has not gained therapeutic utility in the treatment of biliary diseases.

Pancreatic enzymes and salts of UDCA complement one another in the digestive system of a mammal. A dietary supplement containing both the enzymes and salts of UDCA would provide in a convenient pre-determined dose the remedy needed to treat the above-described diseased states. However, the acidic form of UDCA is incompatible with pancreatic enzymes. Pancreatic enzymes/UDCA compositions have a pH of about 5 to 5.5. Under these acidic conditions most pancreatic enzymes show a low biological activity of about 10% to 40%. Lipase is especially affected by the low pH for the reasons that: UDCA is only sparingly soluble in aqueous media and is inefficient to emulsify fats; and the acidic UDCA inactivates lipase since lipase requires a basic pH for biological activity.

Pancreatic enzymes/UDCA containing compositions also lack sufficient shelf-life due to the denaturing and detergent effects of UDCA on the pancreatic enzymes. Because of these incompatibilities between UDCA and pancreatic enzymes the many benefits derivable from their combinations could not be realized by the prior art.

It has now been discovered that the problems associated individually with enteric coated microtablets and microspheres containing pancreatic enzymes and compositions containing UDCA, may be overcome in a dietary supplement containing both the pancreatic enzymes and a salt of UDCA. In accordance with the discovery, UDCA is first converted to a pharmaceutically acceptable salt, such as the sodium or potassium salt and then used in a combination with pancreatic enzymes in a composition. Such salts are highly effective to emulsify fats and lipids at a basic pH and facilitate the hydrolysis of the emulsified fat globules. As a result, fat digestion is greatly enhanced. The salts are also more effective than the insoluble acidic form of UDCA to lyse mucus which blocks the intestinal surfaces and prevents absorption of metabolites that results in poor nutrition in cystic fibrosis children.

Pancreatic enzymes then are combined with a salt of UDCA and buffered with a biologically compatible, pharmaceutically acceptable buffer that prevents deactivation of the enzymes and preserves the natural biological activities of both the enzymes and the salt of UDCA. The pancreatic enzymes/salt of UDCA composition can be prepared into microtablets and microspheres in the presence of moisture without inactivation of the enzymes/bile salt composition thereby resulting in products that do not crumble upon drying or disintegrate upon initiation of the polymer coating procedure. The bitter taste and associated gastric disadvantages of UDCA salts are also eliminated by the polymer coating which prevents solubilization of the product in the mouth and stomach of the patient.

Still further, it has been discovered that microspheres in the range of 10 to 80 mesh size (about 2.0 to 0.177 mm range) can be prepared utilizing bile salts as seeds to build up the microspheres. Such small particle size microspheres are especially beneficial for use to treat pancreatic enzymes/bile salt deficiencies in cystic fibrosis children.

SUMMARY OF THE INVENTION

The invention will be described with particular reference to salts of ursodeoxycholic acid, however, it is to be understood that salts of other bile acids and salt complexes thereof including their isomers may be used as well.

In accordance with the present invention, digestive enzymes/salt of UDCA compositions are provided which possess desirable characteristics heretofore absent in proposed or existing prior art products.

The digestive enzymes/salt of UDCA is instantly soluble in water, while UDCA alone or in combination with a digestive enzyme is essentially insoluble.

Only the ionized or salt form of UDCA or the conjugated derivatives of UDCA are absorbed from the intestine, while the acidic form of UDCA is insoluble and passes through the intestine intact, unless it is converted to the sodium salt by the intestinal buffers. However, many patients, such as patients with cystic fibrosis, pancreatitis, Billroth I & II diseases and some elderly people, are partially deficient in bicarbonate secretion and lack neutralization capacity to convert the acidic form of UDCA to the sodium salt of UDCA. These patients will only partially benefit from UDCA therapy. The salt of UDCA-containing composition of the present invention overcomes this problem by being instantly soluble in the intestinal juices and absorbable from the intestine. Additionally, the composition also provides extra buffering capacity to neutralize the acid chyme that is present in the intestine and greatly facilitates the efficient digestion of fats and lipids in the upper intestine.

The digestive enzymes/salt of UDCA composition is microencapsulated and coated with an acid-resistant polymer-coating, which protects the composition from gastric acid and from conversion of the salt of UDCA to the acidic form of UDCA. The polymer-coated microcapsules are tasteless and the problem associated with the offensive bitter taste of the uncoated acidic form or the uncoated salt of UDCA is thereby alleviated.

The microcapsules uniformly disperse with the food in the stomach and deliver high levels of biologically active digestive enzymes/salts of UDCA into the duodenum. Once in the duodenum, the polymer coating dissolves within about 10 to 30 minutes and the enzymes/salts of UDCA are released to enhance digestion of fats and lipids. As a result, the natural digestive conditions in the intestine are re-established. Epigastric pain, cramps, bloating, flatulence and stool frequency associated with maldigestion of fatty foods are reduced.

Soluble salts of UDCA and conjugated derivatives of UDCA are absorbed more efficiently and in a greater quantity from the intestine than the insoluble acidic form of UDCA, resulting in a more efficient stimulation of the liver enzymes to conjugate ursodiol (UDCA). The increased concentration of the conjugated ursodiol stimulates bile flow, enhances the displacement of toxic bile acid metabolites from the hepatocytes, decreases cholesterol secretion into bile, alters the cholesterol/phospholipid ratio of secreted bile and decreases the absorption of dietary cholesterol from the intestine. The overall result is decreased biliary cholesterol saturation, increased bile flow, dissolution of already formed cholesterol gallstones and protection of the liver from accumulated toxic metabolites.

The digestive enzymes/salt of UDCA composition for the treatment of enzyme/UDCA deficient mammals comprises a blend of ingredients and a coating expressed in weight per weight percentages based on the total weight of the composition:

a) from about 71 to about 90.0% of a concentrate of an enzyme selected from the group consisting of pancreatic proteases, lipases, nucleases and amylases;

b) from about 0.3 to about 13% of a UDCA salt in powder or microsphere form;

c) from about 0.8 to about 5% of a buffering agent selected from the group consisting of about 0.25 to about 5.0% sodium carbonate (anhydrous powder), sodium bicarbonate, potassium carbonate, potassium bicarbonate and ammonium carbonate and from about 0.25 to about 1.5% tromethamine, diethanolamine and triethanolamine;

d) from about 0.5 to about 8% of a disintegrant selected from the group consisting of starch and modified starches, microcrystalline cellulose and propylene glycol alginate;

e) from about 0.3 to about 10% of an adhesive polymer selected from the group consisting of polyvinylpyrrolidone, microcrystalline cellulose, hydroxypropyl cellulose, cellulose acetate phthalate and a 60:40 blend of methyl cellulose and hydroxypropyl methyl cellulose; and

f) from about 7.0 to about 15% of a non-porous, pharmaceutically acceptable gastric acid-resistant polymer-coating which contains less than 2% talc and which is insoluble in the pH range of from about 1.5 to about 5 but is soluble in the pH range of from about 5.5 to about 9.

The digestive enzymes of the present invention includes Pancreatin of multiple strength, Pancrelipase, Trypsin, Chymotrypsin, Chymotrypsin B, Pancreatopeptidase, Carboxypeptidase A, Carboxypeptidase B, Glycerol Ester Hydrolase, Phospholipase A2, Sterol Ester Hydrolase, Ribonuclease, Deoxyribonuclease, α-Amylase, Papain, Chymopapain, Bromelain, Ficin, β-Amylase, Cellulase and β-Galactosidase (Lactase).

The salts of UDCA includes sodium, potassium, ammonium, tromethamine, ethanolamine, diethanolamine and triethanolamine salts or salt complexes.

In accordance with the present invention, the enzyme/bile salt composition is prepared by a process comprising the steps of:

a) blending dry, powdery ingredients selected from the group consisting of (i) from about 71 to about 90% w/w of an enzyme from the group consisting of pancreatic proteases, lipases, nucleases and amylases; (ii) from about 1.0 to about 13% w/w of a salt or salt complexes of UDCA selected from the group consisting of sodium, potassium, ammonium, tromethamine, ethanolamine, diethanolamine and triethanolamine; (iii) a buffering agent selected from the group consisting of from about 0.25 to about 5.0% w/w sodium carbonate (anhydrous), sodium bicarbonate, potassium carbonate, potassium bicarbonate and ammonium carbonate, and from about 0.25 to about 1.5% w/w, tromethamine, diethanolamine and triethanolamine; (iv) of from about 0.5 to about 8.0% w/w a disintegrant selected from the group consisting of starch and modified starches and microcrystalline cellulose and propylene glycol alginate; and (v) from about 0.3% to about 10% w/w of an adhesive polymer selected from the group consisting of polyvinylpyrrolidone, cellulose acetate phthalate, hydroxypropyl cellulose and methylcellulose;

b) wetting said blended ingredients with a liquid to cause the blend to stick together, wherein said liquid is selected from the group consisting of: 1%-25% w/w ethanol/75%-99% w/w 2-propanol/0.2%-2% w/w water; 98%-99% w/w 2-propanol/0.2%-2% w/w water; 1%-25% w/w methanol/0.2%-2% w/w water/75%-98% w/w 2 propanol/1%-5% w/w ethylacetate;

c) granulating or extruding the liquid-wetted blend through a 10 or a 18 mesh S/S screen;

d) converting the granules to a uniform diameter particle size;

e) compacting the uniform particles to spherical particles;

f) drying the spherical particles;

g) separating the spherical particles if not of uniform size according to desired sizes using U.S. Standard sieve screens;

h) coating the particles with a gastric acid-resistant polymer that dissolves under neutral or slightly basic conditions; and

i) drying the polymer-coated spherical particles.

DETAILED DESCRIPTION OF THE INVENTION

In preparing the pancreatic enzymes/bile salt containing microspheres of the present invention utilizing the extrusion, uni-sizer and marumerization process (later described) moisture must be included in the liquid or solvent-adhesive composition to render the adhesive polymer sticky enough to bind the enzymes/bile salt-containing fluffy powder into a pliable, solid mass. This prevents the crumbling of the microspheres during the drying and coating steps as well as allows the preparation of much smaller particle size microspheres, i.e. in the range of 10 to 80 mesh. Accordingly, it was found that the moisture level during the preparation of the composition should be in the range of from about 0.2% w/w to about 2.5% w/w, preferably, in the range of 0.2% w/w to 1.5% w/w, and most preferably in the range of 0.2% w/w to 1.0% w/w. When the compositions contained such amounts of moisture, the microspheres were found to be stable on aging and biological activity was preserved as long as the moisture level did not exceed about 2.5% w/w of the total composition.

Further reference is now made to the process of preparing compositions of the present invention.

The process for the manufacture of microspheres consists of:

1) Blending the dry, powdery ingredients together in a conventional blender and wetting the composition with a suitable liquid composition, hereinbefore described, that causes the dry blend to stick together. The stickiness of the blend can be tested by compressing a handful of the blend in the palm of the hand. If the composition is compressible and sticks together but readily crumbles when squeezed between the fingers, sufficient liquid has been added to the composition for processing in the subsequent granulation step.

2) Granulating or extruding the liquid moistened composition through a 10 or a 18 mesh S/S screen using an oscillating/reciprocating granulator or a twin-screw extruder at a medium-to-high speed.

3) Classifying the granulated particles in a so-called "uni-sizer vessel" that rotates at 15 to 45 rpm for about 5 to 10 minutes. (The particles in the "unisizer vessel" are converted to a uniform diameter particle size.)

4) Compacting the uniform particles in a marumerizer, (a cylindrical vessel with a rotating disk at the bottom) for about 15 to 70 seconds. An alternative method of compacting the microspheres can also be achieved in a rotating conventional coating pan. In this case, the particles are tumbled in the pan for about 15 to 30 minutes, occasionally wetting the particles with a fine mist of the liquid composition.

5) Drying the spherical particles in an oven under a stream of warm and dry air not exceeding 35° C. and 40% relative humidity.

6) Separating the microspheres according to the desired sizes using U.S. Standard sieve screens.

7) Coating the desired and classified microspheres (for example, in the 16 to 20 mesh and separately in the 30 to 60 mesh size range) with an acid-resistant polymer in fluidized bed coating equipment, or in a conventional coating pan according to standard operating procedures as described in the manufacturer's instruction manual.

8) Drying the polymer coated microspheres in an oven under a stream of warm and dry air not exceeding 35° C. and 40% relative humidity until all the volatile substances (moisture and solvents) are removed.

The following examples will further serve to illustrate the compositions of the present invention wherein the compositions and the process of preparing them will be described with reference to microsphere forms; however, it is to be noted that the microtablet form of the composition and the process of making it is also intended to be covered by the present invention. The process of making the microtablet form of the composition is analogous to that of making the microspheres with the exception that the 40 to 80 mesh particles are compressed together into microtablets of 0.5 mm to 2.5 mm with a suitable tablet press and polymer coated, and should be understood by those skilled in the art.

EXAMPLE I Generalized Formula Composition (polymer coated)

______________________________________Ingredients         % w/w______________________________________Disintegrant        0.9-16%Salt of Bile acid   0.3-13%Buffering agent (anhydrous)               0.8-5%Enzymes             90.0-71%Adhesive Polymer    0.3-19%Polymer coat/talc mixture               7.0-15%______________________________________
EXAMPLE II Formula Composition

______________________________________            IIA (uncoated)                        IIB (coated)Ingredients      % w/w       % w/w______________________________________Disintegrant     3.0         2.7Sodium Ursodeoxycholic acid            5.3         4.7Buffering agent (anhydrous)            1.0         0.9Enzymes          89.3        79.7Adhesive Polymer 1.4         1.3Polymer coat/talc mixture    10.7______________________________________
EXAMPLE III Formula Composition

______________________________________            IIIA (uncoated)                        IIIB (coated)Ingredients      % w/w       % w/w______________________________________Disintegrant     3.0         2.7Sodium-Ursodeoxycholic acid            5.3         4.7Buffering agent (anhydrous)            1.0         0.9Enzymes          89.3        79.7Adhesive Polymer 1.4         1.3Polymer coat/talc mixture    10.7______________________________________
EXAMPLE IV Formula Composition

______________________________________             IVA (uncoated)                         IVB (coated)Ingredients       % w/w       % w/w______________________________________Disintegrant      2.0         1.8Potassium-Ursodeoxycholic acid             1.5         1.4Buffering agent (anhydrous)             2.0         1.8Enzymes           90.5        83.1Adhesive Polymer  4.0         3.6Polymer coat/talc mixture     8.3______________________________________
EXAMPLE V Pancreatic Enzyme/Bile Salt Composition

______________________________________Ingredients           % w/w______________________________________Bile salt starting seed (20-40 mesh)                 12.8%Disintegrant          2.3%Buffering agent (anhydrous)                 2.1%Enzymes               65.0%Adhesive polymer mixture                 7.1Polymer coat/talc mixture                 10.7______________________________________

The bile salt starting seeds in Example V were prepared as outlined in Example VII. Suitable bile acids, bile salts and bile acid esters to prepare starting seeds in the particle size range of 20-60 mesh are: Ursodeoxycholic acid; sodium, potassium and ammonium salts of ursodeoxycholic acid; ethyl and propyl esters of ursodeoxycholic acid; glycyl and tauroursodeoxycholic acid; sodium, potassium and ammonium salts of glycyl and tauroursodeoxycholate; N-methyl glycyl ursodeoxycholate and N-methyl tauroursodeoxycholate.

              TABLE I______________________________________Distribution of the Microspheres According to Sizes             Example IIB  Example IIIBMesh Size    (mm)     Microspheres (%)                          Microspheres (%)______________________________________10       2.00     --           3.520       0.84     10.0         57.040       0.42     53.8         32.760       0.25     28.6         5.280       0.177     7.6         1.6______________________________________

              TABLE II______________________________________Moisture Content & Stability of the Microspheres  IIB           IIIB    Moisture   Stability                        Moisture StabilityMesh Size    Content (%)               (4 mo.)* Content (%)                                 (4 mo.)*______________________________________20       1.1        99%      1.6      98%40       0.9        98%      1.9      96%60       0.8        100%     2.5      95%80       0.9        98%      2.7      85%______________________________________ *Lipase, Amylase and Protease Activities assayed according to USP XXII.
EXAMPLE VI Preparation of Salts of Ursodeoxycholic Acid

In general, UDCA was converted to the sodium or potassium salt (Na-UDCA, K-UDCA) by dissolving UDCA in a suitable solvent and titrated with a water soluble alkaline hydroxide, carbonate or bicarbonate solutions (e.g. sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate solutions, etc.) until the pH has reached pH 8.6. The solvent was removed by evaporation or by distillation and the UDCA-salt was recovered from the media by spray drying or by lyophilizing the remaining solution.

In a more detailed process, 20 g of UDCA was dissolved in 100 ml of alcohol (methanol, ethanol, isopropanol or an other suitable alcohol that was easily removed after UDCA has been neutralized) and a 10%-30% solution of hydroxide, bicarbonate or carbonate solution of Na, K, etc. was added to the reaction mixture, with rigorous mixing. The UDCA solution was titrated until the pH reached 8.6. The alcohol was removed from the reaction mixture on a rotary evaporator, and the aqueous solution was processed to recover the solid Na-UDCA by lyophilization or by spray-drying.

In a modified procedure, a cation exchange resin in the sodium form (AMBERLITE IRC-72)was used to prepare the Na-UDCA. The resin was suspended in methanol. The methanol/cation exchange resin was poured into a 4 cm×40 cm column and washed with 500 ml of methanol to remove traces of water. A 5% solution of UDCA in methanol was passed through the resin, followed by washing the column with 200 ml of methanol. The eluent was collected, the methanol evaporated and the Na-UDCA was collected as fine crystals.

EXAMPLE VII Preparation of Bile Salt Starting Seeds

______________________________________          % w/w______________________________________Bile Salt        60.7Disintegrant     16.0Buffering agent  4.6Adhesive polymer 18.7______________________________________

The process of making the bile salt-containing starting seeds consisted off 1) blending the bile salt, disintegrant and the buffering agent together for 10 minutes; 2) spraying the composition with the adhesive polymer mixture until the powdery blend agglomerated; and 3) granulating or extruding the liquid moistened composition through a 10 or 18 mesh S/S screen using an oscillating/reciprocating granulator or a twin-screw extruder. The subsequent processing steps were the same as outlined in Steps (3) through (6) in the "Detailed Description of the Invention".

Referring to ingredients used in the above examples:

Suitable Disintegrant in Examples I through V and Example VII are: Explotab (Mendell, Inc.), microcrystalline cellulose, and propylene glycol alginate (Kelco Co.)

Suitable Buffering Agents in Examples I through V and Example VII are: sodium carbonate (anhydrous), sodium bicarbonate, potassium carbonate, potassium bicarbonate, ammonium carbonate, tromethamine, diethanolamine and triethanolamine.

Suitable Enzymes in Examples I through V and Example VII are: Pancreatin, Pancrelipase and Pancreatin concentrates of high potency.

Suitable Bile Salts in Examples I through V and Example VII are: sodium and potassium salts of ursodeoxycholate, glycyl and taurine ursodeoxycholate, N-methyl glycyl and N-methyl tauroursodeoxycholate, and organic complexes of tromethamine, diethanolamine and triethanolamine of ursodeoxycholate, glycyl and taurine ursodeoxycholate and N-methyl glycyl and N-methyltaurine ursodeoxycholate.

Suitable Adhesive Polymeric Agents in Example I through V and Example VII are: Hydroxypropyl cellulose (Klucel HF, Hercules Co.), polyvinyl pyrrolidone (Plasdone, GAF Co.), a 60:40 blend of methyl cellulose and ethyl cellulose (Dow Chem. Co.), Hydroxypropyl methyl cellulose (Grades 50 and 55, Eastman Kodak Co.), cellulose acetate phthalate (Eastman Kodak Co.) and propylene glycol alginate (Kelco Co.).

Suitable Acid-Resistant Polymers to coat the microspheres in Example I through V and Example VII are: Hydroxypropyl methyl cellulose phthalate, Grades 50 and 55 (Eastman Kodak Co., or Shin-Etsu Chemical Co., Ltd.), AQUATERIC® aqueous enteric coating polymer dispersion (FMC Corp.), EUDRAGIT® acrylic based polymeric dispersion (Rohm Pharma GMBH, Germany), and cellulose acetate phthalate (Eastman Kodak Co.).

Example VIII will further illustrate the composition of the acid-resistant polymer-coating:

EXAMPLE VIII

______________________________________                  % w/w______________________________________Hydroxypropyl methyl cellulose phthalate*                    7.4Diethyl phthalate        2.02-Propanol               45.2Ethylacetate             45.2Talc, USP                0.2______________________________________ *When the hydroxypropyl methyl cellulose phthalate was replaced with cellulose acetate phthalate an equally suitable acidresistant polymer coating was obtained, as long as, talc was also included in the composition. The presence of talc with the film forming polymer caused th deposition of an acidimpermeable polymer coat. When AQUATERIC ® or EUDRAGIT ® aqueous enteric coating polymer dispersion was employed in place of cellulose acetate phthalate (CAP) or hydroxypropyl methyl cellulose phthalate (HPMCP), the microspheres were first sealed with an initial thin layer coating with CAP or HPMCP (2-4% w/w of the microspheres), followed by a secondary coating with an aqueous polymeric latex disperson (for example, AQUATERIC ® or EUDRAGIT ®). The employment of the aqueous coating composition as a secondary coating is important to reduce the evaporation of solvents into the atmosphere and thus reduce environmental pollution.

The total amount of the composition required to be administered to an enzyme/bile salt deficient patient will vary with the severity of the conditions, age and other physical characteristics of the patient. The physicians will prescribe the total amount, the dosage and the frequency of dosage administration on a patient by patient basis. Generally, for enzyme/bile salt deficient patient from about 0.5 to about 1.5 grams of the composition are administered with each major meal, three times a day. Larger amount may, however, be required for certain conditions, such as for dissolving gallstones.

For ease of administration of the compositions it is preferred to use gelatin capsules containing about 0.2 to 0.5 grams microspheres or microtablets. Gelatin capsules which disintegrate in the acidic environment of the stomach are well-known and utilized in the prior art. Microtablets are of small size, having a diameter between about 1 to 5 mm and a thickness between 0.5 to 4 mm. The microtablet is prepared by conventional tableting procedure. However, the compositions of the present invention in the form of very small particle sizes may be used per se. The microspheres shown in Example IIB and IIIB (Table I) are in the 10 to 80 mesh size range. Table I shows that 100% of the microspheres of Example IIB were in the 20 mesh to 80 mesh size range (0.84 to 0.149 mm) and 89.7% of the coated particles IIIB were in the range of 20 to 40 mesh size range (0.84 to 0.42 mm). Young children or adults with certain diseases are unable to swallow big gelatin capsules. Microspheres of very small size of the present invention could then be administered to the patients with liquid food, such as milk, apple sauce and semi-solid foods.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3004893 *Oct 21, 1959Oct 17, 1961Richardson Merrell IncEnteric coated trypsin and chymotrypsin anti-inflammatory compositions
US3065142 *Jul 30, 1958Nov 20, 1962Armour PharmaGastric resistant medicinal preparation
US4011169 *Jan 28, 1976Mar 8, 1977The Procter & Gamble CompanyStabilization and enhancement of enzymatic activity
US4079125 *Nov 26, 1976Mar 14, 1978Johnson & JohnsonGastric juice insoluble, intestinal juice soluble
US4280971 *Oct 31, 1979Jul 28, 1981Kali-Chemie Pharma GmbhProcess for the production of pancreatin pellets
US4447412 *Feb 1, 1983May 8, 1984Bilton Gerald LPancreatic and proteolytic enzymes, choleretic agent, hydrochloride, and pepsin
US4828843 *Jun 24, 1988May 9, 1989Basf AktiengesellschaftUniform size, pancreatin
US4944944 *Nov 19, 1987Jul 31, 1990Oklahoma Medical Research FoundationFor increasing fat absorption and animal growth; infant formulas
US5013557 *Oct 3, 1989May 7, 1991Warner-Lambert CompanyAntiulcer agents
US5234697 *Jun 22, 1992Aug 10, 1993Digestive Care Inc.Compositions of gastric acid-resistant microspheres containing salts of bile acids
US5260074 *Jun 22, 1992Nov 9, 1993Digestive Care Inc.Compositions of digestive enzymes and salts of bile acids and process for preparation thereof
US5262172 *Jun 19, 1992Nov 16, 1993Digestive Care Inc.Compositions of gastric acid-resistant microspheres containing buffered bile acids
USRE30910 *Jan 31, 1980Apr 20, 1982Intellectual Property Development CorporationAdministering 3a,7b-dihydroxy-5b-cholanic acid
GB1296944A * Title not available
GB1362365A * Title not available
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US5415872 *Oct 20, 1993May 16, 1995Digestive Care Inc.Compositions of gastric acid-resistant microspheres containing salts of bile acids
US5750104 *May 29, 1996May 12, 1998Digestive Care Inc.Buffer added for side effect reduction while maintaining enzyme activity
US6251428Jul 20, 1999Jun 26, 2001Seo Hong YooPreparation of aqueous clear solution dosage forms with bile acids
US7166299Dec 4, 2002Jan 23, 2007Seo Hong YooComprises ursodeoxycholic acid for treating gastritis and peptic ulcer disease
US7303768Feb 5, 2001Dec 4, 2007Seo Hong YooGastrointestinal disorders; antiulcer agents
US7772220Oct 14, 2005Aug 10, 2010Seo Hong YooMethods and compositions for reducing toxicity of a pharmaceutical compound
US7833963Jun 3, 2003Nov 16, 2010Sarantis Pty LtdFor use as an anticancer agent and an immunosuppressive agent
US7932243Mar 10, 2006Apr 26, 2011Seo Hong YooBile preparations for gastrointestinal disorders
US8008036Sep 25, 2008Aug 30, 2011Curemark, LlcMethod for identifying autistic individuals amenable to digestive enzyme therapy
US8012710Jun 19, 2009Sep 6, 2011Curemark, LlcMethods of treating and diagnosing Parkinsons disease and related dysautonomic disorders
US8012930Mar 11, 2008Sep 6, 2011Curemark, LlcMethods of treating pervasive development disorders
US8030002Nov 16, 2001Oct 4, 2011Curemark LlcMethods for diagnosing pervasive development disorders, dysautonomia and other neurological conditions
US8071089 *Oct 31, 2006Dec 6, 2011Bio-Cat, Inc.Composition with a fungal (yeast) lipase and method for treating lipid malabsorption in cystic fibrosis as well as people suffering from pancreatic lipase insufficiency
US8084025Apr 20, 2009Dec 27, 2011Curemark LlcMethod for the treatment of the symptoms of drug and alcohol addiction
US8105584Sep 8, 2008Jan 31, 2012Curemark LlcMethod for treating pervasive development disorders
US8163278Oct 8, 2003Apr 24, 2012Curemark LlcAdministering secretin based on chymotrypsin level; attention deficit disorder, hyperactivity, autism
US8173627Aug 30, 2005May 8, 2012Seo Hong YooNeuroprotective effect of solubilized UDCA in focal ischemic model
US8211661Jun 19, 2009Jul 3, 2012Curemark, LlcMethod for identifying individuals having a pervasive development disorder amenable to digestive enzyme therapy
US8221747 *Feb 20, 2008Jul 17, 2012Aptalis Pharma LimitedStable pancreatic enzyme compositions
US8246950 *Feb 20, 2008Aug 21, 2012Aptalis Pharma LimitedStable digestive enzyme compositions
US8293229 *Feb 20, 2008Oct 23, 2012Aptalis Pharma LimitedDigestion enzyme such as pancrealipase; gastrointestinal disorders ; core with enteric coating mixture of polymer, alkalinity agent and moisture; delay releasing particles
US8318158Oct 12, 2011Nov 27, 2012Curemark, LlcPharmaceutical preparation for the treatment of the symptoms of addiction and method of diagnosing same
US8486390Jul 31, 2012Jul 16, 2013Curemark LlcPharmaceutical preparation for the treatment of the symptoms of addiction and method of diagnosing same
US8562978 *Jul 8, 2010Oct 22, 2013Aptalis Pharma LimitedStable digestive enzyme compositions
US8562979 *Feb 2, 2011Oct 22, 2013Aptalis Pharma LimitedStable digestive enzyme compositions
US8562980Feb 2, 2011Oct 22, 2013Aptalis Pharma LimitedStable digestive enzyme compositions
US8562981Feb 2, 2011Oct 22, 2013Aptalis Pharma LimitedStable digestive enzyme compositions
US8580522Aug 12, 2011Nov 12, 2013Curemark, LlcMethods for diagnosing pervasive development disorders, dysautonomia and other neurological conditions
US8613918May 25, 2012Dec 24, 2013Curemark LlcMethod for treating pervasive development disorders
US8658163Mar 13, 2008Feb 25, 2014Curemark LlcCompositions and use thereof for treating symptoms of preeclampsia
US8673877Aug 8, 2011Mar 18, 2014Curemark, LlcUse of lactulose in the treatment of autism
US8772691Apr 16, 2010Jul 8, 2014Abl Ip Holding LlcOptical integrating cavity lighting system using multiple LED light sources
US8778335Mar 11, 2008Jul 15, 2014Curemark, LlcMethods of treating and diagnosing Parkinson's disease and related dysautonomic disorders
US8815233Apr 16, 2012Aug 26, 2014Curemark LlcMethod for treating pervasive development disorders
US20100270183 *Jul 8, 2010Oct 28, 2010Eurand Pharmaceuticals LtdStable digestive enzyme compositions
US20110123633 *Feb 2, 2011May 26, 2011Eurand Pharmaceuticals LtdStable digestive enzyme compositions
WO2010120781A1 *Apr 13, 2010Oct 21, 2010Curemark LlcEnzyme delivery systems and methods of preparations and use
Classifications
U.S. Classification424/94.63, 424/94.6, 424/497, 424/94.1, 424/94.65, 424/94.64
International ClassificationA61K9/50, A61K38/46, A61K9/16
Cooperative ClassificationA61K38/48, A61K38/47, A61K38/465, A61K9/5073, A61K9/5042, A61K9/5026, A61K9/1605
European ClassificationA61K9/50K, A61K9/50H6F2, A61K9/16H, A61K38/46, A61K9/50H6B
Legal Events
DateCodeEventDescription
Aug 15, 2005FPAYFee payment
Year of fee payment: 12
Nov 5, 2001FPAYFee payment
Year of fee payment: 8
May 8, 1998SULPSurcharge for late payment
May 8, 1998FPAYFee payment
Year of fee payment: 4